PTC Recognition in Human Nonsense-mediated mRNA Decay

控制我们体内细胞生长和增殖的信息包含在染色体的基因中。大多数基因在细胞核中指导信使rna （mrna）的转录。mRNA转录后，在细胞核中进行进一步的加工，包括通过剪接过程去除称为内含子的非编码片段。经过充分加工的mrna随后被输出到细胞质中，在那里它们作为由核糖体介导的蛋白质生产的模板。有时，当mRNA被加工时，会发生错误，导致mRNA编码异常缩短的蛋白质产物。这对细胞是有害的，因为在某些情况下，即使是少量的缩短蛋白产物也会阻碍全长蛋白正常发挥作用的过程。然而，真核细胞已经进化出一种机制来识别和降解这种异常mrna，从而防止它们产生缩短的蛋白质产物。这种机制被称为无义介导的mRNA衰变（NMD）途径。NMD途径识别异常mrna的机制尚不清楚，且存在高度争议。在本项目中，将研究NMD机制如何与核糖体合作，识别编码缩短蛋白的异常mRNA，以及这如何受到细胞核中mRNA剪接过程的影响。该项目将培养两名研究生，其中包括一名女学生。此外，两到三名本科生和一名或多名高中生将接触到生物学研究。该项目是首席研究员在科罗拉多大学博尔德分校分子生物学本科和研究生教学的一个组成部分。该项目还将产生几种试剂，以帮助其他研究人员推进该领域的研究。

The information that controls the growth and multiplication of cells in our body is contained within the genes of their chromosomes. Most genes direct the transcription of messenger RNAs (mRNAs) in the nucleus of the cell. After the mRNA is transcribed it undergoes further processing in the nucleus, which includes removal of non-coding segments called introns by the process of splicing. Fully processed mRNAs are then exported to the cytoplasm where they serve as templates for production of proteins mediated by the ribosome. Sometimes when mRNAs are processed, mistakes happen that cause the mRNA to encode aberrantly shortened protein products. This can be deleterious to cells, as even small amounts of shortened protein products can in some cases block the process in which the full-length protein normally functions. However, eukaryotic cells have evolved a machinery to identify and degrade such aberrant mRNAs, thus preventing their production of shortened protein products. This machinery is called the nonsense-mediated mRNA decay (NMD) pathway. The mechanism by which the NMD pathway identifies aberrant mRNAs is poorly understood and highly debated. In this project, it will be studied how the NMD machinery cooperates with the ribosome to identify aberrant mRNAs that encode shortened proteins, and how this is influenced by the process of mRNA splicing in the nucleus.This project will train two graduate students, including a female student. In addition, two or three undergraduate students and one or more high-school students will be exposed to biological research. This project is an integral part of the principal investigator's undergraduate and graduate teaching in Molecular Biology at the University of Colorado, Boulder. This project should also generate several reagents that will help other researchers advance this field of research.